Three patients were found who had endogenous IgG which bound to mouse IgG resulting in factitiously high serum TSH concentrations using a two site sandwich IRMA based on mouse monoclonal antibodies. This phenomenon was studied and described to an extent greater than previously reported. It was determined that this interference can occur in any IRMA based on mouse antibodies but is usually blocked by the inclusion of non-specific mouse immunoglobulins in the test system. IgG Fc fragments are more potent than either F(ab')2 or Fab in blocking the interference due to heterophile antibodies. This suggests that use of Fab or F(ab')2 fragments instead of whole mouse IgG in formulating sandwich assays may reduce the frequency or amount of interference. One patient was found who escapes the usual blockade provided by inclusion of mouse Ig in the assay kit.